PROJECT SUMMARY West Nile virus (WNV) is a significant cause of neuronal injury and inflammation that results in severe disease that can potentially be lethal. In order to reduce or eliminate invading viruses from the central nervous system (CNS) and protect the brain, it is vital that T cells enter the virally-infected CNS and perform their anti-viral functions. However, due to the sensitivity of neurons, the presence activated T cells within the CNS may also contribute to neuropathology if not rigorously regulated. Previous research showed that dendritic cells (DCs) are critical for establishing virologic control within the CNS during WNV neuro-invasive disease. Yet, little is known as to how these cells accomplish protection without causing neuronal damage. We hypothesize that a specific subset of DCs (DEC-205-expressing DCs) promote virologic control and protection against WNV neuro-invasive disease through the appropriate activation of the T cells migrating into the virally-infected CNS. To address this hypothesis, we will use a well-established mouse model of WNV encephalitis, where one experimental group will be genetically deficient for the DEC-205 gene, effectively eliminating this subset of DCs from the brain and elsewhere. Using this model, we will be able to determine the role of these cells in limiting viral infection, replication, and neuronal injury within the WNV-infected CNS. We will also perform an adoptive transfer of these cells into the genetically deficient mice at a critical stage during WNV neuro-invasive disease. Through this study, we will determine the mechanisms by which this specific subset of DCs provide protection against WNV neuro- invasive disease. Together, these studies will illuminate and enhance our understanding of our immune responses to viral infections in the brain and the balance between an effective immune response and immunopathology with injury to neurons. It also has clear implications for the control and prevention of WNV neuro-invasive disease.